Z. Cai, L.-J. Yan / Journal of Biochemical and Pharmacological Research, Vol.

1 (1): 15-26, March 2013

Review

Protein Oxidative Modifications: Beneficial

Roles in Disease and Health
Zhiyou Caia, Liang-Jun Yanb,*

Abstract: Protein oxidative modifications, also known as

protein oxidation, are a major class of protein
posttranslational modifications. They are caused by
reactions between protein amino acid residues and reactive
oxygen species (ROS) or reactive nitrogen species (RNS)
and can be classified into two categories: irreversible
modifications and reversible modifications. Protein
oxidation has been often associated with functional decline
of the target proteins, which are thought to contribute to
normal aging and age-related pathogenesis. However, it has
now been recognized that protein oxidative modifications
can also play beneficial roles in disease and health. This
review summarizes and highlights certain positive roles of
protein oxidative modifications that have been documented
in the literature. Covered oxidatively modified protein
adducts
include
carbonylation,
3-nitrotyrosine,
s-sulfenation, s-nitrosylation, s-glutathionylation, and
disulfide formation. All of which have been widely analyzed
in numerous experimental systems associated with redox
stress conditions. The authors believe that selected protein
targets, when modified in a reversible manner in
prophylactic approaches such as preconditioning or
ischemic tolerance, may provide potential promise in
maintaining health and fighting disease.
Keywords: carbonylation, cysteine, glutathionylation,
ischemic tolerance, nitrosylation, nitrotyrosine, sulfenation,
sulfenic acid, postconditioning, preconditioning, oxidative
modifications, reactive oxygen species

__________________________________________
a

Department of Neurology, Lu'an People's Hospital, the Lu'an

Affiliated Hospital of Anhui Medical University, Lu'an, Anhui
Province, China, 237005
b
Department of Pharmacology and Neuroscience and Institute for
Aging and Alzheimer's Disease Research, University of North Texas
Health Science Center, Fort Worth, Texas, USA
* Corresponding author. Tel: +1 817-735-2386; Fax: +1 817-735-0408
Email: liang-jun.yan@unthsc.edu
(Received January 10, 2013; Revised February 4, 2013; Accepted
February 4, 2013; Published online February 5, 2013)

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1. Introduction

n order to cope with environmental challenges, cells rely on a

variety of posttranslational modification mechanisms to
expand protein function [1-4]. Of all the documented
posttranslational modifications, oxidative modification of the
side chains of various amino acid residues forms a major
category of protein posttranslational modifications [5-7].
Protein oxidative modifications can be generally classified into
two categories: irreversible oxidation and reversible oxidation
[8-10]; both of which can be selectively induced by reactive
oxygen species (ROS) and reactive nitrogen species (RNS) [11,
12].
Earlier studies of protein oxidation nearly exclusively
focused on the detrimental effects of protein oxidation in aging
and diseases [5, 9, 13-17]. It has now been firmly recognized,
however, that protein oxidation can also play a positive role in
many cellular functions. This gradual realization of the
beneficial roles of protein oxidation may be attributed to
accumulating evidence that ROS and RNS are indispensible for
cell survival [18-22] and regeneration [23], and in many cases,
they are required for recovery of cellular functions by creating
positive stress conditions whereby cell survival mechanisms
are reprogrammed to extend life span [24-27] or to withstand
severe, or lethal challenges [28-31].
In this article, we review both irreversible and reversible
oxidative modifications that are beneficial in health and
disease. Modification adducts to be discussed include protein
carbonyls, 3-nitrotyrosine, and cysteine oxidation products
(Fig. 1). As protein cysteine residue is the one that often
undergoes reversible redox modifications by ROS or RNS
[32-34], we have inclined to devote more space on cysteine
modifications including s-sulfenation, s-nitrosylation,
s-glutathionylation, and disulfide formation that are all
reversible [35-38]. It should be noted that protein oxidative
modifications that have deleterious effects in health and disease
are beyond the scope of this review and will only be
sporadically mentioned.

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2. Cellular sources of oxidants

There are many systems inside a cell that can generate ROS.
Mitochondria are recognized as the major site for ROS
production [39-41]; and both complexes I and III have been
established to be the specific sites for mitochondrial ROS
generation [42-45]. Besides mitochondria, many enzymes are
also capable of producing ROS. These include, but not limited
to, NADPH oxidase [46, 47], xanthine oxidase [48, 49],
-ketoglutarate dehydrogenase complex [50-52], d-amino acid
oxidases [53-55], and dihydrolipoamide dehydrogenase
[56-62]. On the other hand, nitric oxide production in vivo is
mainly achieved by nitric oxide synthases [63-65] though under
certain conditions deoxygenated myoglobin [66] or xanthine
oxidoreductase [67] or cytochrome c oxidase [68] can be
involved in NO production; and in vitro nitric oxide donors are
also frequently used either in experimental systems [69-71] or
for therapeutic purpose [72-74]. It should be noted that in the
presence of superoxide anion, nitric oxide can rapidly react
with superoxide anion to yield peroxynitrite [75-77], a reactive
species that is highly reactive toward redox-sensitive amino
acid residues including tyrosine and cysteine [78, 79].

Nitrotyrosine, usually 3-nitrotyrosine, is formed between

reactive nitrogen species and a proteins tyrosine residue [78,
98, 99]. This modification is a highly selective process as not all
proteins or all tyrosine residues on a target protein can get
nitrated [100]. Formation of nitrotyrosine is often thought to be
accompanied with acute or chronic inflammation disease
[101-104], whereby level of nitric oxide is elevated [102,
104-106]. While numerous studies have investigated the
deleterious effects of 3-nitrotyrosines [107, 108], concurrent
with development of methods for detection and quantitation
[109, 110], this modification has been detected under normal
physiological conditions such as healthy pregnancy [111, 112],
indicating that formation of 3-nitrotyrosine has physiological
function.
Carbonyls (carbonylation)

3-nitrotyrosine

Irreversible

Protein
Reversible

3. Irreversible protein oxidative modifications

First, we would like to discuss briefly the possible beneficial
role of irreversible modifications. These types of modifications
include mainly protein carbonylation and tyrosine nitration [11,
80-84]. Both modifications are often associated with oxidative
damage and have been used as biomarkers for assessment of
oxidative stress in aging and diseases [13, 15-17, 85]. While
both carbonylation and nitration can have detrimental effects
on the target proteins, evidence has also emerged that such
modifications can also play positive roles in cellular function
under stress conditions.
3.1. Protein carbonyls
Protein carbonyls formed on several amino acids residues,
including arginine, histidine, lysine, proline, threonine and
cysteine, are the most widely used biomarker for measurement
of protein oxidation and oxidative stress in aging and diseases
[5, 8, 11-14, 86-90]. As the modification occurs on multiple
amino acid residues on selected protein targets [15-17, 91], its
magnitude is much greater than any other modifications that
occur only on a specific amino acid residue [11, 12], and thus is
more readily detectable. Many studies have employed protein
carbonylation to evaluate the detrimental effects of protein
oxidation and oxidative stress [13-16, 87-90]; evidence for
positive effects of this modification, however, has started to
accumulate. For example, protein carbonylation has been
shown to be involved in signal transduction [92-95] and is
known to be involved in ischemic preconditioning eliciting
protection against reperfusion-induced tissue injuries [96, 97].
3.2. Protein nitrotyrosine

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Sulfenic acid
(s-sulfenation)

disulfides
s-nitrosothiols
S-nitrosylation)
s-glutathione
(s-glutathionylation)

Fig. 1. Irreversible and reversible protein oxidation products discussed

in this review. Irreversible oxidation includes protein carbonyls and
3-nitrotyrosine while reversible oxidation includes cysteine
modification products such as sulfenic acid, nitrosothiols, and
s-glutathione.

4. Reversible protein oxidative modifications: protein

cysteine modifications
4.1. Chemistry of protein cysteine residues
At neutral pH under physiological conditions, free cysteine
residues have a pKa value that is around 8.5, which makes
oxidative modifications impossible [113]. To be susceptible to
oxidation, the pKa value of a cysteine residue needs to be lower
than the physiological pH value (pH 7.4), a condition under
which, the cysteine SH group becomes thiolated (thiolate
anion) [113-115]. It is those thiolated cysteine residues that are
redox reactive [35, 116]. This thiolation process, decreasing the
pKa value to 7.2 or lower, can be achieved via many factors
such as hydrogen bonding [117, 118], the effect of adjacent
basic amino acid residues [117], the microenvironment of the
target cysteine residues [117], and substrate binding [119]. For

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Z. Cai, L.-J. Yan / Journal of Biochemical and Pharmacological Research, Vol. 1 (1): 15-26, March 2013

example, albumin cysteine 34 has a very low pKa value of 5

[120]. Hence under physiological condition, it exists as thiolate
anion and is very reactive towards oxidants, thiols, metals, and
disulfides [121-123].
As described above, thiols with low pKa values are more
reactive because they are usually deprotonated or thiolated at
physiological pH [124-126]. Therefore, oxidation of protein
cysteines that are redox reactive is also a highly selective
process [127, 128]. As shown in Fig. 2, cysteine oxidation
usually starts with the formation of sulfenic acid, from which a
variety of oxidation products can be furtherly formed and many
of them are reversible and well defined chemically. These
cysteine oxidation products include disulfide formation (S-S-),
S-glutathionylation (protein-SSG), S-nitrosylation (-SNO),
sulfenic acid formation (-SOH, or S-sulfenation) and have all
been demonstrated in redox regulation of protein functions by
ROS and RNS [35, 129, 130]. Importantly, all of which have
been implicated to play beneficial roles in disease and health
because they may protect the target proteins from further
oxidation that will otherwise permanently damage the target
proteins [131-133]. Another mechanism is that these
modifications also play a role in redox signaling cascades that
boost cellular defense systems to better counteract stress insults
[134-136].

peroxynitrite [38, 129, 137, 142, 143]. Although being a simple

chemical modification, sulfenic acid formation can have a
dramatic effect on protein function [130, 137, 144]. It was for a
long time regarded as an intermediate, unstable cysteine
oxidation product, which may still be true for many proteins
[137, 145, 146]. Growing evidence, however, has demonstrated
that stable-SOH indeed exists, making trapping, labeling,
detecting, and quantitating possible for further evaluation of the
formed SOH [142, 147-150]. A beneficial effect of protein
SOH formation has been elegantly demonstrated in studies
whereby s-sulfenation of aldose reductase protects the heart
against ischemic/reperfusion injury [151-153]. Specifically,
these studies found that cyse-298s sulfenation of aldose
reductase by peroxynitrite shows great protection against
cardiac ischemic injury; and administration of peroxynitrite
scavengers not only eliminates cys-298s sulfenation, but also
abolishes cardiac protection against ischemic injury. In
unrelated studies, Michalek et al. demonstrated that protein
sulfenation is indispensible for T-cell growth and proliferation
as arrest of sulfenic acids greatly impairs T cell maturation
[154]. Another example of a beneficial role of P-SOH is that of
the sulfenation of nitrile hydratase; sulfenic acid formation on
this enzymes Cys114 residue is absolutely essential for the
enzymes catalytic activity [155].
4.3. Protein s-nitrosylation

S-S-G
SNO

Reversible

GSH

H2 O
HNO

NO

HS

.
S

ROS

S-S

SOH

Irreversible

ROS

SO2H

ROS

SO3H

Fig. 2. Chemistry of cysteine oxidative modifications. Sulfenic acid is

truly an intermediate product during cysteine oxidation. Given
appropriate conditions, s-nitrosothiols can also be discomposed to
yield sulfenic acids with concurrent production of nitroxyl [137].
Sulfenic acid can be further oxidized to form disulfide bonds,
s-glutathionylation. Irreversible oxidation products sulfinic and
sulfonic acids are also shown.

Protein s-nitrosylation can be induced by nitric oxide,

nitroxyl, and peroxynitrite [156, 157]. This modification has
been regarded as functionally equivalent to protein
phosphorylation and dephosphorylation [158-160]. Besides
occurring on cysteine residues other than on tyrosine, serine, or
threonine residues, s- nitrosylation is also potentially different
from phosphorylation in that nitrosylation may not involve a
delicate network consisting of kinases or enzymes that catalyze,
respectively, nitrosylation and denitrosylation, though the
existence of denitrosylases, including Cu,Zn-superoxide
dismutase and bilirubin, has been reported [161-165].
Nonetheless, s-nitrosylation has been demonstrated to be a key
modification of cysteine residues under a variety of
physiological and pathophysiological conditions [157, 166,
167]. In particular, in connection with nitric oxide-based redox
regulation of protein function, s-nitrosylation has been found to
be involved in protective mechanisms in many disorders [157,
168-170]. For example, Sheng et al. have demonstrated that
chemically-enhanced s-nitrosylation can improve recovery
from subarachnoid hemorrhage [171], and Penna et al. have
demonstrated that protein s-nitrosylation is favorably produced
during cardiac postconditioning [172].
4.4. Protein s-glutathionylation

4.2. Protein sulfenic acid formation (S-sulfenation)

This sulfur-hydroxylation product (P-SOH) possesses
powerful redox chemistry and has been demonstrated to play a
key redox regulatory role in a growing number of proteins [34,
138-141]. Its formation is mainly induced by ROS such as
hydrogen peroxide, alkyl hydroperoxides, and RNS such as
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Protein
cysteine
residues
can
also
undergo
s-glutathionylation under oxidative stress conditions [173-175].
Glutathione (GSH) is the major cellular antioxidant, yet, it can
also modify proteins via mixed disulfide formation (P-S-S-G),
leading to functional changes of the target proteins [176]. This
reversible oxidation of critical cysteine residues on proteins has

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Z. Cai, L.-J. Yan / Journal of Biochemical and Pharmacological Research, Vol. 1 (1): 15-26, March 2013

been found to be involved in oxidative signal transduction,

control of gene expression, cell proliferation, apoptosis, and
cellular responses to protecting key regulatory molecules from
oxidative insults [173, 176-178]. Similar to s-sulfenation and
s-nitrosylation, protein-S-S-G is also often associated with a
detrimental effect on the target proteins function [179-182],
but can also protect the target protein from irreversible and
permanent
damage
[183-186].
Therefore,
protein
glutathionylation has increasingly gained great attention as a
possible means of redox regulation of protein functions in
response to oxidative stress under physiological and
pathophysiological conditions [185, 187]. For example, actin
glutathionylation
regulates
actin
dynamics
in
polymorphonuclear neutrophils [188], manipulation of
uncoupling protein 2s glutathionylation may provide a strategy
for cancer treatment [189], and glutathionylation of adenine
nuclear translocase induced by preconditioning can prevent
mitochondrial membrane permeabilization and apoptosis [190].
4.5. Protein disulfides
This is different from protein s-glutathionylation, where a
mixed disulfide between GSH and a protein-linked cysteine
residue is formed [191-193]. Native disulfide bond formation is
usually involved in correct protein folding and is catalyzed by
disulfide isomerase in the endoplasmic reticulum and the
mitochondrial intermembrane space [194-197], and should be
considered different from those formed under oxidative stress
or pathophysiological conditions. Hence herein, disulfide
formation is strictly meant to reflect inter- or intra- protein
disulfide formation that is caused by ROS or RNS [198-205].
Disulfide bonds formed between free cysteine residues upon
oxidative stress have been reported to play a beneficial role in
cellular defense systems against a variety of stress challenges
[191, 206-210]. For example, intra-protein disulfide formation
in Cdc25c upon hydrogen peroxide exposure regulates the
stability of the protein [211], and in the brain type creatine
kinase, disulfide formation between two cysteine residues
(cys74 and cys254) can serve as a cellular defense mechanism
[212]. Additionally and importantly, it is well established that
formation of disulfide linkage within Keap1 in response to
cellular stimuli by electrophiles and oxidants [213-217] is
essential for activation of the NF-E2-related factor 2 (Nrf2) that
then upregulates the expression of phase II antioxidant
enzymes under a variety of physiological and
pathophysiological conditions [218-224].
5. Protein oxidative modifications and ischemic tolerance
Posttranslational protein oxidative modifications, in
particular cysteine modifications, have been implicated in
ischemic tolerance or preconditioning [168, 225-231]. Ischemic
tolerance constitutes a positive stress that reporgrams cellular
defense systems to prevent subsequent lethal injuries
[232-237]. The phenomenon of preconditioning seems to be
universal as all tissues in mamalian systems as well as all
organisms can be preconditioned. In particular, the heart and
the brain can be preconditioned by a variety of mechanisms to
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prevent further injuries caused by ischemia reperfusion [232,

238]. Therefore, preconditioning has both prophylactic and
therapeutic value. Despite intensive studies, the mechanisms of
preconditioning has not been well understood. Nonetheless,
ROS are known to be the key molecules involved in
preconditioning development [239-243] as antioxidants
administered during induction of preconditioning can block the
preconditioning
effect
[28,
30].
Moreover,
a
moderately-elevated level of ROS, in particular, H2O2, has been
shown to be neuroprotective [221, 244-246]. Nevertheless, how
ROS work in preconditioning induction and tissue protection
remains elusive. As ROS can impart their effects by modifying
proteins, identification of endogenous protein targets of ROS
may elucidate mechanisms of protection induced by ischemic
tolerance. It is thus conceivable that identification of
oxidatively modified protein targets, especially those that can
undergo reversible oxidative modifications, may provide
insights into novel therapeutic strategies for ischemic tolerance.
It is also worth mentioning that a concept of postconditioning,
whereby the reperfusion procedure can be disrupted and
intervened to elicit protection against lethal injury, has been
recently established [247-250]. We think that postconditioning
can also be placed under the notion of ischemic tolerance. In
fact, preconditioning and postconditioning may share similar
pathways or mechanisms [250-254].
So why could protein oxidation, in particular, reversible
oxidation-induced by ischemic tolerance be involved in
protection against subsequent ischemic injury? As it is the
reperfusion stage that often incurs the injury due to a sudden
burst in ROS production concurrent with resupply of oxygen
[255-259], oxidized proteins with altered protein function
could slow down the rate of ROS production during reperfusion
and hence could attenuate ischemic injury [230, 260]. In
addition, as already pointed out earlier in this review, oxidized
proteins induced by ischemic tolerance could also be involved
in eliciting cellular defense systems to protect against further
severe ischemia reperfusion injury [261, 262].
6. Summary and Perspectives
While studies on the detrimental or deleterious effects of
protein oxidative modifications are, and will still be,
dominating the field of protein oxidation, investigation of the
beneficial roles of protein oxidation appears to be gaining
increasing interest [135, 263]. For beneficial purposes, efforts
should be focused on proteomic identification of reversibly
oxidized proteins that may exhibit protective effects. Further,
studies on a comprehensive understanding of the mechanisms
or pathways that regulate the reversible nature of the
corresponding modifications should be undertaken. This should
be particularly true for reversible cysteine oxidation, which not
only reflects changes in cellular redox state, but can also protect
the target proteins from further damage. Additionally,
reversible cysteine oxidation is also involved in redox signaling
cascades [264-267] that can elicit positive stress responses to
prevent unpredicted disastrous events such as stroke and heart
attack. Therefore, equal efforts will also be needed to identify
those protein targets that undergo reversible cysteine

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Z. Cai, L.-J. Yan / Journal of Biochemical and Pharmacological Research, Vol. 1 (1): 15-26, March 2013

modifications in preventative or protective approaches as such

identified protein targets may provide therapeutic values in
fighting diseases, in particular, ischemia associated cerebral
and cardiovascular diseases.
Acknowledgments

[16]
[17]

[18]

The authors wish to apologize to those whose work could

not be cited due to space limitations. LJY was supported in part
by the National Institutes of Health (Grant: AG022550) and by
the University of North Texas Health Science Center
(UNTHSC-UAEM seed grant: RI6044).

[19]

[20]

Conflict of interest: None declared.

[21]

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